Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years.

BACKGROUND AND OBJECTIVES: Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures. RESULTS: The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD. DISCUSSION: Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose. TRIAL REGISTRATION INFORMATION: The study is registered at ClinicalTrials.gov as NCT01730170.

Early Identification of Candidates for Epilepsy Surgery: A Multicenter, Machine Learning, Prospective Validation Study.

BACKGROUND AND OBJECTIVES: Epilepsy surgery is often delayed. We previously developed machine learning (ML) models to identify candidates for resective epilepsy surgery earlier in the disease course. In this study, we report the prospective validation. METHODS: In this multicenter, prospective, longitudinal cohort study, random forest models were validated at a pediatric epilepsy center consisting of 2 hospitals and 14 outpatient neurology clinic sites and an adult epilepsy center with 2 hospitals and 27 outpatient neurology clinic sites. The models used neurology visit notes, EEG and MRI reports, visit patterns, hospitalizations, and medication, laboratory, and procedure orders to identify candidates for surgery. The models were trained on historical data up to May 10, 2019. Patients with an ICD-10 diagnosis of epilepsy who visited from May 11, 2019, to May 10, 2020, were screened by the algorithm and assigned surgical candidacy scores. The primary outcome was area under the curve (AUC), which was calculated by comparing scores from patients who underwent epilepsy surgery before November 10, 2020, against scores from nonsurgical patients. Nonsurgical patients' charts were reviewed to determine whether patients with high scores were more likely to be missed surgical candidates. Delay to surgery was defined as the time between the first visit that a surgical candidate was identified by the algorithm and the date of the surgery. RESULTS: A total of 5,285 pediatric and 5,782 adult patients were included to train the ML algorithms. During the study period, 41 children and 23 adults underwent resective epilepsy surgery. In the pediatric cohort, AUC was 0.91 (95% CI 0.87-0.94), positive predictive value (PPV) was 0.08 (0.05-0.10), and negative predictive value (NPV) was 1.00 (0.99-1.00). In the adult cohort, AUC was 0.91 (0.86-0.97), PPV was 0.07 (0.04-0.11), and NPV was 1.00 (0.99-1.00). The models first identified patients at a median of 2.1 years (interquartile range [IQR]: 1.2-4.9 years, maximum: 11.1 years) before their surgery and 1.3 years (IQR: 0.3-4.0 years, maximum: 10.1 years) before their presurgical evaluations. DISCUSSION: ML algorithms can identify surgical candidates earlier in the disease course. Even at specialized epilepsy centers, there is room to shorten the time to surgery. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a machine learning algorithm can accurately distinguish patients with epilepsy who require resective surgery from those who do not.

Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy.

Importance: The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated. Objective: To examine the association of fetal ASM exposure with subsequent adaptive, behavioral or emotional, and neurodevelopmental disorder outcomes at 2, 3, and 4.5 years of age. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational cohort study conducted at 20 epilepsy centers in the US. A total of 456 pregnant women with epilepsy or without epilepsy were enrolled from December 19, 2012, to January 13, 2016. Children of enrolled women were followed up with formal assessments at 2, 3, 4.5, and 6 years of age. Statistical analysis took place from August 2022 to May 2023. Exposures: Exposures included mother's epilepsy status as well as mother's ASM blood concentration in the third trimester (for children of women with epilepsy). Women with epilepsy were enrolled regardless of ASM regimen. Main Outcomes and Measures: The primary outcome was the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children at 4.5 years of age. Children of women with epilepsy and children of women without epilepsy were compared, and the associations of ASM exposures with outcomes among exposed children were assessed. Secondary outcomes involved similar analyses of other related measures. Results: Primary analysis included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). Overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4 [95% CI, -2.5 to 3.4]; P = .77). However, in adjusted analyses, a significant decrease in functioning was seen with increasing third-trimester maximum ASM blood concentrations (PE, -7.8 [95% CI, -12.6 to -3.1]; P = .001). This decrease in functioning was evident for levetiracetam (PE, -18.9 [95% CI, -26.8 to -10.9]; P < .001) and lamotrigine (PE, -12.0 [95% CI, -23.7 to -0.3]; P = .04), the ASMs with sample sizes large enough for analysis. Results were similar with third-trimester maximum daily dose. Conclusions and Relevance: This study suggests that adaptive functioning of children of women with epilepsy taking commonly used ASMs did not significantly differ from that of children of women without epilepsy, but there was an exposure-dependent association of ASMs with functioning. Thus, psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate. Additional research is needed to confirm these findings.

Initiation and Duration of Breastfeeding in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

BACKGROUND AND OBJECTIVES: Breastfeeding has important health benefits for both mother and child. We characterize breastfeeding initiation and duration in mothers with epilepsy relative to control mothers in a large prospective cohort. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a prospective, multicenter observational, US cohort study. Pregnant individuals with and without epilepsy, aged 14-45 years, were enrolled between December 19, 2012, and February 11, 2016. Exclusion criteria included intelligence quotient (IQ) <70, and gestational age >20 weeks at enrollment. Breastfeeding was assessed through electronic diary and at study visits until 2 years postpartum. Odds of initiating breastfeeding was compared between cohorts using unadjusted and adjusted logistic regression models. Duration of breastfeeding was compared between cohorts using the log-rank test. RESULTS: Three hundred fifty-one pregnant individuals with epilepsy and 105 pregnant controls were enrolled. Breastfeeding data were available for 325 mothers with epilepsy and 98 controls. Study cohorts were similar demographically except race (p = 0.008); 84.9% of mothers with epilepsy and 71.4% of controls were White. The mean IQ was lower in mothers with epilepsy compared with that in controls (97.7 vs 104.2, p < 0.001). Breastfeeding was initiated by 74.8% mothers with epilepsy and 88.8% controls; this difference was significant in unadjusted logistic regression (odds ratio [OR] 0.4 [95% CI 0.2, 0.7], p = 0.004), but not in adjusted model (OR 0.5 [95% CI 0.2, 1.0], p = 0.051). Factors associated with breastfeeding were higher maternal education and IQ. There was no difference in duration of breastfeeding between mothers with and without epilepsy (median duration 8.5 months vs 9.9 months, p = 0.793). Among mothers with epilepsy, both convulsive seizures and all seizures that impair awareness during pregnancy were associated with lower breastfeeding initiation (OR 0.4 [95% CI 0.2, 0.8], p = 0.013) and (OR 0.4 [95% CI 0.2, 0.8], p = 0.003, respectively). Any peripartum seizures were associated with shorter breastfeeding duration (median 6 months vs 9.7 months, [p = 0.040]). DISCUSSION: Mothers with epilepsy were less likely to initiate breastfeeding compared with controls; however, this difference was not significant when controlling for maternal IQ and education level. Continuation of breastfeeding once initiated was not different between mothers with and without epilepsy. Seizure control was associated with breastfeeding initiation and duration in mothers with epilepsy. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT01730170.

Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study.

BACKGROUND: The neurodevelopmental effects of fetal exposure to most antiseizure medications are unclear. We aimed to investigate the effects of fetal exposure to commonly used antiseizure medications on neuropsychological outcomes at age 3 years. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. We have investigated pregnancy outcomes in women (aged 14-45 years) with and without epilepsy who were enrolled during pregnancy (≤20 weeks' gestational age), and their children. The primary outcome for children at age 3 years was a blindly assessed Verbal Index score, which was calculated by averaging scores on the Naming Vocabulary and Verbal Comprehension subtests of Differential Ability Scales-II, Expressive Communication and Auditory Comprehension subscales of Preschool Language Scale-5, and Peabody Picture Vocabulary Test-4. Children of women with and without epilepsy were compared, and the associations of medication exposures to outcomes in exposed children were assessed. The MONEAD study is registered with ClinicalTrials.gov, NCT0730170, and is ongoing. FINDINGS: Between Dec 19, 2012, and Jan 13, 2016, 456 pregnant women (351 with epilepsy and 105 without epilepsy) were enrolled into the study. 345 children were born to women with epilepsy and 106 children were born to women without epilepsy. Verbal Index scores at age 3 years did not differ for children of women with epilepsy (n=284; adjusted least-square mean 102·7, 95% CI 101·4 to 103·9) versus those without epilepsy (n=87; 102·3, 99·8 to 104·7). Significant risk factors for reduced Verbal Index scores included maternal intelligence quotient, maternal education, post-birth anxiety, gestational age at enrolment, child's sex, and child's ethnicity. For Verbal Index scores, antiseizure medication exposure effects were not seen for maximum third trimester blood concentrations (n=258; adjusted parameter estimate -2·9, 95% CI -6·7 to 1·0). However, in secondary analyses, exposure-dependent effects were present on multiple cognitive measures, which varied by medication. INTERPRETATION: We found no difference in neurodevelopmental outcomes between children with fetal exposure to newer antiseizure medications compared with unexposed children. However, some exposure-dependent antiseizure medication effects were seen in secondary analyses. The adverse effects of maternal post-birth anxiety emphasise the importance of screening mothers during pregnancy and postpartum and implementing interventions. Additional studies are needed to clarify the exposure-dependent effects. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health and Development.

Prospective Cohort Study of Depression During Pregnancy and the Postpartum Period in Women With Epilepsy vs Control Groups.

BACKGROUND AND OBJECTIVES: Assess the incidence and factors associated with major depressive episodes (MDEs) and symptoms of depression and anxiety during pregnancy and postpartum periods in pregnant women with epilepsy (PWWE) compared with healthy pregnant women (HPW) and nonpregnant women with epilepsy (NPWWE) in comparable timeframes. Previous studies have reported higher rates of postpartum depression in women with epilepsy compared with women without epilepsy. However, the incidence of MDE using a structured interview during pregnancy and postpartum has not been directly compared with control groups, and the comparison of depression and anxiety symptoms and the role of associated factors remain ambiguous. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational parallel group cohort study of PWWE and their children. This report examines mood disorders. Unlike previous epilepsy pregnancy studies, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) provided lifetime diagnoses, and repeated SCID mood modules assessed for MDE, the a priori primary outcome. Symptoms of depression (Beck Depression Inventory [BDI] and Edinburg Postnatal Depression Scale [EPDS]) and anxiety (Beck Anxiety Inventory [BAI]) were also assessed along with multiple clinical factors. RESULTS: This study included PWWE (n = 331) and HPW (n = 102) during pregnancy and postpartum and NPWWE (n = 102) at comparable times. No difference in SCID-diagnosed MDE incidence was found across groups, but BDI depressive symptoms were worse during pregnancy in PWWE vs NPWWE and during postpartum vs HPW and NPWWE. BAI anxiety symptoms were worse during pregnancy in PWWE vs HPW and NPWWE and during postpartum vs HPW. Factors associated with MDE during pregnancy/postpartum for PWWE included >1 seizure/90 days, anticonvulsant polytherapy, unplanned pregnancy, and lifetime history of mood disorder. Suicidal ideation from BDI or EPDS was related to BAI anxiety symptoms. DISCUSSION: Although SCID-based MDE did not differ across groups, this prospective study confirms higher rates of psychiatric symptoms in patients with epilepsy during pregnancy and postpartum, provides new data on associated factors, and underscores the importance of anxiety in risk for depression and thoughts of death/dying or suicide. Given the risks, PWWE should be routinely assessed and symptomatic patients should be offered treatment. TRIAL REGISTRATION INFORMATION: This study is registered at ClinicalTrials.gov as NCT01730170.

The Effect of Epilepsy on Sleep Quality During Pregnancy and Postpartum.

OBJECTIVE: This study seeks to understand how sleep is affected in pregnant women with epilepsy (WWE) relative to healthy pregnant women during pregnancy and postpartum and to non-pregnant WWE during comparative time periods. BACKGROUND: Sleep impacts maternal health and mood during pregnancy. Maternal sleep disturbances are related to poor fetal growth and increased fetal deaths. Epilepsy is the most common neurologic condition in pregnancy. Sleep disruption can worsen epileptic seizures. The interplay between epilepsy, pregnancy, and sleep is poorly understood. DESIGN: /Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter study, enrolling women from December 2012 through January 2016. Sleep quality was assessed utilizing the average Pittsburgh Sleep Quality Index collected during pregnancy; postpartum; or analogous time periods. Sleep scores range from 0 to 21 with higher scores indicating worse sleep quality; scores > 5 are associated with poor sleep quality. RESULTS: Of 351 pregnant WWE, 105 healthy pregnant women, and 109 non-pregnant WWE enrolled in MONEAD, data from 241 pregnant WWE, 74 healthy pregnant women, and 84 non-pregnant WWE were analyzed. Pregnant WWE had worse sleep (higher mean sleep score) during pregnancy compared to healthy pregnant women in unadjusted analysis (p=0.006), but no longer significant in adjusted analysis (p=0.062), pregnant WWE (least square mean sleep score (95% CI) = 5.8 (5.5, 6.1)) vs. healthy pregnant women (5.1 (4.6, 5.7)). During postpartum, pregnant WWE (5.6 (5.4, 5.9)) had similarly impaired sleep compared to healthy pregnant women (5.7 (5.2, 6.2); adjusted p=0.838). Sleep was significantly worse in pregnant WWE vs non-pregnant WWE (for comparable time period) in pregnancy and postpartum in unadjusted and adjusted analyses. Adjusted scores for pregnant WWE in pregnancy (5.7 (5.4, 6.0)) and postpartum (5.7 (5.4, 6.0)) compared to non-pregnant WWE (4.7 (4.2, 5.3); p=0.002) and (4.1 (3.6, 4.7); p<0.001), respectively. Sleep quality between pregnancy and postpartum varied only in healthy pregnant women (change in mean score = 0.8 (0.2, 1.3); p=0.01), whose sleep was worse in postpartum. CONCLUSIONS: Pregnant WWE had worse sleep during pregnancy and postpartum than non-pregnant WWE during comparable periods in the adjusted analysis.The study is registered at clinicaltrials.gov as NCT01730170.

Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

Importance: The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs). Objective: To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020. Main Outcomes and Measures: Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed. Results: The BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05). Conclusions and Relevance: Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women. Trial Registration: ClinicalTrials.gov Identifier: NCT01730170.

Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy.

BACKGROUND: Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups. METHODS: In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy) (epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the two groups during the first 9 months of epoch 1. RESULTS: We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the two epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 pregnant women (23%) and in 23 controls (25%) (odds ratio, 0.93; 95% confidence interval [CI], 0.54 to 1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82 to 10.59). CONCLUSIONS: Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.).

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy.

Importance: There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy. Objective: To provide direct, objective information on antiepileptic drug exposure through breast milk. Design, Setting, and Participants: This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019. Exposures: Antiepileptic drug exposure in infants who were breastfed. Main Outcomes and Measures: The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle. Results: A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants. Conclusions and Relevance: Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

Fetal loss and malformations in the MONEAD study of pregnant women with epilepsy.

OBJECTIVE: To examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016. RESULTS: The 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04-19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65-12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046). CONCLUSIONS: The findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.

Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy.

OBJECTIVE: We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14-45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) <70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment. RESULTS: Three hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each <1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each <4%); only 5.2% of polytherapy subjects were on ≥3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy). CONCLUSIONS: The distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.

Which patients with epilepsy are at risk for psychogenic nonepileptic seizures (PNES)? A multicenter case-control study.

OBJECTIVE: We sought to examine the clinical and electrographic differences between patients with combined epileptic (ES) and psychogenic nonepileptic seizures (PNES) and age- and gender-matched patients with ES-only and PNES-only. METHODS: Data from 138 patients (105 women [77%]), including 46 with PNES/ES (39±12years), 46 with PNES-only (39±11years), and 46 with ES-only (39±11years), were compared using logistic regression analysis after adjusting for clustering effect. RESULTS: In the cohort with PNES/ES, ES antedated PNES in 28 patients (70%) and occurred simultaneously in 11 (27.5%), while PNES were the initial presentation in only 1 case (2.5%); disease duration was undetermined in 6. Compared with those with ES-only, patients with PNES/ES had higher depression and anxiety scores, shorter-duration electrographic seizures, less ES absence/staring semiology (all p≤0.01), and more ES arising in the right hemisphere, both in isolation and in combination with contralateral brain regions (61% vs. 41%; p=0.024, adjusted for anxiety and depression) and tended to have less ES arising in the left temporal lobe (13% vs. 28%; p=0.054). Compared with those with PNES-only, patients with PNES/ES tended to show fewer right-hemibody PNES events (7% vs. 23%; p=0.054) and more myoclonic semiology (10% vs. 2%; p=0.073). CONCLUSIONS: Right-hemispheric electrographic seizures may be more common among patients with ES who develop comorbid PNES, in agreement with prior neurobiological studies on functional neurological disorders.

Improving the prescription of folate to women receiving antiepileptic drugs.

In women of childbearing potential (WCP) on antiepileptic drugs (AEDs), there is an increased risk of teratogenicity. This can potentially be reduced with folate supplementation. We evaluated the rate of co-prescription of AEDs and folate to WCP by non-epileptologist Neurology attendings and residents before and after an educational intervention. During the initial 3 month survey, 54 WCP were prescribed ≥1 AEDs. Prior to the intervention, the rate of co-prescription of AEDs and folate was 20.4%. This was higher when neurologists were prescribing AEDs for epilepsy (34.4%) versus other disorders (0%, p=0.02). In the 3 months following the intervention, 48 WCP received AEDs. The rate of co-prescribing folate increased to 64.6% (p<0.001). Neurologists treating epilepsy continued to be more likely to prescribe folate (86.4%) than neurologists treating other conditions (46.2%, p=0.006).

Levetiracetam induces a rapid and sustained reduction of generalized spike-wave and clinical absence.

BACKGROUND: Levetiracetam (LEV) is a new antiepileptic drug with efficacy in partial-onset seizures. We report a case in which generalized-onset absence seizures responded clinically and electrographically to LEV. METHODS: We evaluated with continuous video/electroencephalography an adult with generalized-onset seizures given 3 antiepileptic drugs, 1 of which was LEV. Levetiracetam initiation 2 months before admission decreased patient-reported seizures. Interictal electroencephalography revealed generalized 3.5-Hz spike-wave and polyspike-wave discharges. Spike-wave bursts lasting 2 seconds or longer caused a pause in continuous reading aloud, consistent with clinical absence seizures. Levetiracetam was discontinued on admission, lamotrigine was gradually discontinued across 2 days, and topiramate was not changed. One encephalographer counted from video/electroencephalography recordings the number of spike-wave bursts in 1-hour time samples that included wake and sleep time. RESULTS: Spike-wave bursts increased from 4 to 56 per hour at baseline (4000 mg of LEV per day) to 406 to 914 per hour less than 48 hours after LEV discontinuation. Levetiracetam treatment was restarted, and 3 hours after the first dose of 1000 mg, spike-wave bursts dropped to 135 per hour. Response was sustained during the next 2 days. CONCLUSIONS: This case showed a dramatic, rapid effect of LEV discontinuation and reinstitution on generalized spike-wave burst frequency and clinical absence. The effects were independent of reduction of lamotrigine and without change in topiramate doses and occurred in a time course consistent with LEV pharmacokinetics. Levetiracetam may be effective in generalized-onset epilepsy, and randomized, controlled trials are indicated.